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ejbps, 2018, Volume 5, Issue 6 865-877.

SJIF Impact Factor 4.918

2349-8870 European Journal Biomedical Europeanof Journal of Biomedical and Pharmaceutical ISSN Sciences Volume: 5 Issue: 6 AND Pharmaceutical sciences

Rajwant et al.

865-877 Year: 2018

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SYNTHESIS AND PHARMACOLOGICAL ACTIVITIES OF 1,3,4-OXADIAZOLE DERIVATIVES: A REVIEW Rajwant Kaur* and Parminder Kaur University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali. *Corresponding Author: Rajwant Kaur University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali.

Article Received on 19/04/2018

Article Revised on 09/05/2018

Article Accepted on 30/05/2018

ABSTRACT Among different five member heterocyclic systems Pyrrole, Oxadiazole, Thiadiazole, Triazole and their derivatives have gained importance as they constitute the structural features of many bioactive compounds. Among them 1,3,4-oxadiazole are of significant interest in medicinal chemistry. 1,3,4-oxadiazole is a highly privileged structure and its derivatives exhibit a wide range of biological activities including antibacterial, antitubercular, vaso-dialatory, antifungal, cytotoxic, anti-inflammatory and analgesic, hypo-lipidemic, anti-cancer and ulcero-genic activities. Furamizole is a compound which is based upon 1,3,4-oxidiazole ring and has strong Antibacterial Activity. KEYWORDS: 1,3,4-oxadiazole, 1,2,4-oxadiazole, Heterocyclic Chemistry, Pharmacological activities. INTRODUCTION Heterocyclic compound contributes to the major percentage of privileged structures for the designing of new drugs is a very effective approach. Oxadiazole is a five member heterocyclic having two nitrogen, one oxygen and two double bonds. Oxadiazole moiety and its various derivatives studied frequently in the past few decades and found potent in various pharmacological and pathological conditions.[1] Among different five members heterocyclic systems pyrrole, oxadiazole, thiadiazole, triazole and their derivatives have gained importance as they constitute the structural features of many bioactive compounds. Among them 1,3,4-oxadiazoles are of significant interest in medicinal chemistry. Literature reveals that 1,3,4-oxadiazole is a highly privileged structure and its derivatives exhibit a wide range of biological activities including antibacterial, anti-tubercular, vasodialatory, antifungal, cytotoxic, anti-inflammatory and analgesic, hypolipidemic, anti-cancer and ulcerogenic activities. Furamizole is a compound which is based upon 1,3,4oxidiazole ring and has strong antibacterial activity.[2]

1

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Oxadiazole derivatives have been found to Posses broad spectrum antimicrobial activity and therefore are useful substructure for further molecular exploration. [3] Isomeres of oxadiazole Oxadiazole exist in four isomeric forms depending on the position of nitrogen atom in the ring as shown below.[3]

1,2,4-Oxadiazole

1,2,3-oxadiazole

1,3,4-oxadiazole

1,2,5-oxadiazole

Chemistry of Oxadiazole Ainsworth prepared 1,3,4-oxadiazole in 1965 by the thermo-lysis of ethyl formate formly hydrazine at atmospheric pressure.[4]

Chemical Reactivity of 1,3,4-Oxadiazole Electrophilic substitution reaction Due to low electron density on the carbon atom, Electrophilic attack is favorable at 3rd position and results

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in the formation of 1,3,4-oxadiazolium salts as shown in figure 1. Nucleophilic substitution reaction Nucleophilic attack at ring carbon is a major reaction mode of 1,3,4 –oxadiazole. Such reaction lead to Nucleophilic products 3 or to the ring cleavage with the formation of intermediates 4 and 5, which, in case of Nucleophilies, frequently recyclise into1,2,4-triazole as shown in figure 2.[3]

2 3 Figure 1: Electrophilic substitution reaction of 1,3,4,oxadiazole

Reagents and conditions: (a) Hydrazine hydrate, ethanol, stir, 5 h (b) CS2/KOH, ethanol, reflux (c) secondary amines, ethanol, 8 h Ahsan et al (2011) predicted molecular properties and synthesis of novel 1,3,4-oxadiazole analogues as potent antimicrobial and anti-tubercular agents. In the initial step 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3Hpyrazol-3-one and chloroacetic acid in dry acetone and potassium carbonate refluxed for 8 h giving [(1,5dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) amino] acetic acid. In the subsequent step [(1,5dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) amino] acetic acid was treated with appropriate hydrazide in 5 ml phosphorus oxychloride to furnish the titled compound.[6]

Figure 2: Nucleophilic substitution reaction of 1,3,4oxadiazole Methods for the synthesis of 1,3,4-oxadiazole derivatives The most popular reported method for the synthesis 1,3,4-oxadiazole backbone is the reaction between the properly substituted acid hydrazide, carbon disulphide (CS2) and potassium hydroxide (KOH). Sahoo et al (2014) reported synthesis, characterization and biological evaluation of novel oxadiazole derivatives. New 5-phenyl-1,3,4-oxadiazole-2-thiol derivative was synthesized by the ring closure reactions of benzohydrazides with carbon disulphide in presence of ethanolic KOH followed by substitution with secondary amines.[5]

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Reagents and conditions: (a) Potassium carbonate, dry acetone, reflux, 8 h (b) semicarbazide, phosphorus oxychloride, reflux, 5 h. Sun et al (2011) reported synthesis of oxadiazole derivatives containing 1,4-benzodioxan as potential immunosuppressive agents against RAW264.7 cells. Compound synthesized by refluxing 2,3-dihydrobenzo [b][1,4]dioxine-6-carboxylic acid in methanol containing concentrated H2SO4. Water was added, the organic

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phases were washed with saturated NaCl and dried over Na2SO4, and the solvents were evaporated. In the subsequent step compound was dissolved in dry ethanol and hydrazine hydrate was added and the mixture was refluxed for 8-10 h to give compound. Then a stirred solution of in CH2Cl2 was treated with the appropriate substituted phenyl acetic acid or benzoic acid, EDC.HCl, HOBt with substituted carboxylic acid in phosphoryl chloride or in phosphoryl chloride was refluxed for 5-7 h. Then reaction mixture was cooled, poured into icecold water and neutralized with 20% NaHCO3 solution. The resultant solid was filtered, washed with water and recrystallized from ethanol to give the title compound.[7]

Where R= phenyl, 2-chlorophenyl, 5-bromopyridin-3-yl, 4-nitropheneyl.

Reagents and conditions: (a) Hydrazine hydrate, Ethanol, Reflux, 16-17 h (b) CS2/KOH, ethanol, reflux, 12-12.5 h (c) R-Cl, pyridine, reflux, 4-5 h. Zhang et al (2011) reported synthesis, biological evaluation, and molecular docking studies of 1,3,4oxadiazole derivatives possessing 1,4-benzodioxan moiety as potential anticancer agents. To a stirred solution of and sodium hydroxide in Acetonitrile was added drop wise Acetonitrile containing halogen substituted compounds. The resulting mixture was heated under reflux for 10–24 h and the reaction was monitored by TLC. Afterwards the solution was cooled to room temperature and the organic solvent was removed in vacuum. The residue was dissolved in ethyl acetate and the organic layer was washed with saturated brine. Then the organic phase was dried over anhydrous Na2SO4, filtered, and removed in vacuum. The purification of the residue by recrystallization from Acetonitrile yielded the desired compound.[9]

Reagents and conditions: (a) conc. sulphuric acid, methanol, reflux, 900 C (b) Hydrazine hydrate, Ethanol, Reflux, 900 C (c) Aliphatic or Aromatic carboxylic acids, POCl3, 1100 C (d) EDC. HCl, HOBt, dichloromethane, Room Temperature (e) POCl3, 1000 C. Parikh et al (2011) reported synthesis of 1,3,4oxadiazole derivatives by refluxing methyl salicylate with hydrazine hydrate for 16-17 h. The hydrazide so obtained can be further reacted with carbon disulphide and potassium hydroxide to yield. A mixture of 2-(5sulfanyl-1,3,4-oxadiazol-2-yl)-phenol and different aryl halides were refluxed in pyridine solution for 3.5hours. The resultant mixture was cooled and poured into crushed ice. The solid mass is thus separated out was dried and recrystallized from ethanol to furnish the final compound.[8]

Where R phenyl, 4-fluorophenyl, 4-nitrophenyl, 4chlorophenyl. Reagents and conditions: (a) Concentrated sulfuric acid, methanol, reflux, 8–12 h (b) Hydrazine hydrate (85%), Ethanol, Reflux, 8–12 h (c) CS2/KOH, ethanol (95%), reflux, 24 h (d) NaOH, acetonitrile, reflux, 8–24 h. Gudipati et al (2011) reported synthesis, characterization and anti-cancer activity of certain 3-{4(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino}indolin2-one derivatives. Compound 29 and Isatin were refluxed in 20 ml of ethanol in the presence of a catalytic

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amount of glacial acetic acid (2–3 drops) for 5–6 h and cooled. The solid separated was filtered and washed with cold alcohol and the product obtained was recrystallized from methanol to yield final compound 30. [10]

Reagents and conditions - (a) Anhy.AlCl3 (b) POCl3, RCONHNH2

Succinic

Acid,

Fuloria et al (2010) reported the synthesis of 1-(2ary1-5phenethy1-1,3,4-oxadiazole-3(2H)-y1-ethanones by reacting N-(substituted benzylidene)-3-pheny1 propionohydrazides with acetic anhydride. [13]

Reagents and conditions- (a) Acetic Anhydride

Reagents and conditions: (a) Dry acetone, Ethanol, reflux, 6 h (b) Ac2O, Reflux (c) Hydrazine Hydrate, Ethanol, Reflux, 8 h (d) CS2/KOH, Ethanol, Reflux, 12 h (e) Isatin, glacial acetic acid, ethanol, 5-6 h. Kiselyov et al (2010) reported the synthesis of oxadiazole by refluxing isothiazole derivative with neat hydrazine hydrate for 4 h. The hydrazide so obtained can be further reacted with isothiocyanate followed by in situ cyclization of the intermediate thiosemicarbazide with DCC to afford the key molecules The formation of 1,3,4oxadiazole via condensation of various alkyl hydrazide with substituted acids using various cycloderhydrogenatin agents are reported in literature. A few of them are mentioned below.[11]

Reagents and conditions: (a) NHNH2, Isothiocyanate (c) Thiosemicarbazidereflux,4-6 h

(b)

Kaur et al (2012) reported synthesis of 1,3,4-oxadiazoes by reacting semicarbazide with conc. H2SO4 and then it is kept overnight and then pour it into the ice-cold water. Then it is neutralized with ammonia and extracted with ether.[14]

Reagents and conditions: (a) Conc. Sulphuric acid, Ammonia, kept overnight. Kumar et al (2010) reported synthesis of 1,3,4oxadiazolopyrazolopyrimidine 43 derivative via reaction of 5-amino derivative with methyl-4-(N-(bis (methylthio) methylene) sulfamoyl) phenyl carbamodithioate in dimethylformamide in presence of triethylamine and 1,3,4-oxadiazolopyrazolo pyrimidinone was obtained via reaction of 5-amino derivative with triethylorthoformate as one carbon cyclizing agent.[15]

Husain et al (2010) reported the synthesis of 1,3,4oxadiazole by reacting 4-oxo-4(bipheny1-4y1) butanoic acid (Fenbufen) with ary1 acid hydrazide in phosphorous oxychloride.[12]

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Reagents and conditions: (a) Triethylorthoformate, reflux, 8 h (b) Methyl 4-(N-(bis(methylthio) methylene)sulfamoyl)phenylcarbamo dithioate, triethylamine, DMF, reflux, 5 h. Padmavathi et al (2009) reported synthesis of aminosulfonyl-1,3,4-oxadiazoles by reacting an equimolar mixture of arylaminosulfonylacetic acid, aryl acid hydrazide and benzoic acid in POCl3 and refluxed for 5-8 h. [16]

Reagents and conditions: (a) Hydrazine, ethanol, reflux, 5-6 h (b) Br2\Ac2O, RT, MWI Barbuceanu et al (2010) reported synthesis of oxadiazole by reacting N1-[4-(4-bromophenylsulfonyl) benzoyl]-N4-(4-flourophenyl)-thiosemicarbazide with (a) Mercuric Oxide (HgO) in ethanol (b) I2/KI in NaOH solution.[19]

Where R=H, Me, Cl Reagents and conditions: (a) RC6H4CONHNH2/POCl3 (70-75%) (b) R-C6H4SO2CH2CONHNH2/POCl3 Shirote et al (2010) reported synthesis of some 1,3,4oxadiazoles. Isoniazid was reacted with appropriate acetophenones in methanol with drop of glacial acetic acid and the resulting compound was then treated with acetic anhydride to get the desired 1,3,4-oxadiazoles.[17]

Reagents and conditions: (a) Ethanol, reflux, 10 h (b) thiosemicarbazide, yellow mercuric oxide, ethanol, reflux, 8 h. Prakash et al (2010) reported synthesis of a series of novel 2,5-disubstituted 1,3,4-oxadiazole by oxidative cyclization of pyrazolylaldehyde N-acyl hydrazones promoted by iodobenzene diacetate under mild conditions.[20]

Reagents and conditions: (a) Acetophenones, methanol, reflux, 2 h (b) acetic anhydride, reflux, 2 h; aromatic amines, ethanol, 5-6 h. Kamble et al (2008) reported the microwave assisted synthesis of 1,3,4-oxadiazole from Chalcones. This microwave assisted synthesis lead to the cleaner reactions as well as afforded high yields and shorter reaction times. The Chalcones underwent a rapid cyclization with hydrazine hydrate using Polyethylene glycol (PEG 200) and formic acid as solvents. Further on bromination and heating with acetic anhydride it resulted in the formation of oxadiazole derivatives.[18]

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Reagents and conditions: dichloromethane, stir, RT

(a)

PhI

(OAc)2,

Kumar et al (2008) reported synthesis of novel indolyl1,3,4-oxadiazoles by a neat grinding of indolyl-3aldehyde-N-acyl hydrazone with BTI for 10 min at room temperature.[54]

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Reagents and conditions: (a) CS2/KOH, ethanol, reflux, 6 h. Where R=C6H5, CH2C6H5, 4-pyridyl, 3-pyridyl Reagents and conditions: (a) CH3I, KOH, DMSO, stirring, RT. Saitoh et al (2009) reported synthesis of 1,3,4oxadiazoles by the treatment of aryl acetate with hydrazine hydrate which results in the formation of hydrazide and then treated with carbon disulphide and potassium hydroxide or Et3N to yield oxadiazolethiols.[22]

Reagents and conditions: (a) Hydrazine hydtare, methanol, reflux, 6 h (b) CS2/KOH, ethanol (95%), reflux, 8 h. Milinkevich et al (2009) reported synthesis of 1,3,4oxadiazole exomethylene by diacyl hydrazide as a starting material. Due to the presence of alkenes functionality in the hydrazide a dehydrating reagent was used.[23]

Rai et al (2009) reported synthesis of 2-[1-(5-chloro-2methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5(substituted-phenyl)-[1,3,4]oxadiazoles by reacting substituted pyrazole-4-carbo hydrazide with POCl3 at 120 C overnight.[25]

Where 92a: R = H, R1 = Cl, R2 = H 92b: R = H, R1 = F, R2 = H Reagents and conditions: (a) POCl3, heat, 1200 C Abdel-Aziz et al (2009) reported synthesis of some 1,3,4-oxadiazoles by reacting 1-acylhydrazines with diethyl-2,3-dicyanofumarate in ethyl acetate and refluxed it for a required period of time.[26]

Reagents and conditions: (a) PPh3, Cl3CCCl3, DIEA, CH3CN

Where R=C6H5, thiophene Reagents and conditions: (a) Ethyl acetate, heat, 4-18 h

Idrees et al (2009) reported synthesis of 5-[1-(napthalen2-yloxy) ethyl]-3H-1,3,4-oxadiazole-2-thione via cyclization of the hydrazide with carbon disulphide in refluxing ethanol.[24]

Bhardwaj et al (2009) reported synthesis of some 1,3,4oxadiazoles by reacting hydrazones with chloramines-T in ethanol and refluxed for 7 h. Chloramines-T was added as an oxidizing agent.[27]

Reagents and conditions: (a) chloramine-T

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Kumar et al (2009) reported synthesis of 5-[(biphenyl-4yloxy)-methyl]-2-alkyl/arylamino-1,3,4-oxadiazole by oxidatively cyclization of thiosemicarbazide and elimination of H2S using iodine and potassium iodide in ethanolic sodium hydroxide.[28] Where R = phenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl Reagents and conditions: (a) chloramine-T, ethanol, reflux, 3 h Where R= CH3CH2CH2CH2NHe Reagents and conditions: (a) C2H5OH, KI/I2, 5N NaOH, reflux Rajak et al (2007) reported synthesis of napthalenoxymethylene oxadiazole from a mixture of respective hydrazide, anhydrous sodium acetate and glacial acetic acid and bromine.[29]

Aboraia et al (2006) reported synthesis of 5-(2hydroxyphenyl)-2,3-dihydro-1,3,4-oxadiazole-2-thione by reaction of salicylic acid hydrazide with CS 2 in ethanol in the presence of KOH.[64]

Reagents and conditions: (a) CS2/KOH, HCl, ethanol, reflux, 8 h

Where R= 4-Cl, 4-OH, 4-CH3O, 4-NO2 Reagents and conditions: (a) CH3COOH / Br2, CH3COONa, glacial acetic acid, stir, 1.5 h Kucukguzel et al (2006) reported synthesis of 1,3,4oxadiazole by reacting an appropriate thiosemicarbazide with ethyl bromoacetate in absolute ethanol in the presence of anhydrous sodium acetate.[30]

Reagents and conditions: (a) Br-CH2-COOC2H5, anhyd. CH3COONa, ethanol, reflux, 4-6 h Gaonkar et al (2006) reported synthesis of a new series 2-{4-[2-(5-ethylpyridin-2-yl) ethoxy]phenyl}-5substituted1,3,4-oxadiazoles from aryl hydrazones and chloramine-T.3H2O in ethanol.[31]

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Katritzky et al (2001) reported synthesis of 1-(1,3,4oxadiazol-2-yl methyl)-1H-benzotriazoles. Reaction of the ester with hydrzine reulted in the formation of hydrazides and then hydrazides are reacted with acyl chloride in pyridine and then finally reacted with phosohorous oxychloride.[32]

Reagents and conditions: (a) hydrazine hydrate, ethanol, stir, RT (b) RCOCl, pyridine, reflux, 4 h (c) POCl3, reflux, 5-6 h. Elborai et al (1993) reported synthesis of 2-amino-5-(2thienyl)-1,3,4-oxadiazole by the condensation of 2thienyl hydrazide with CNBr. It is a convenient method of synthesis of amino-1,3,4-oxadiazole because of shorter reaction time.[33]

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Streptococcus pyogenes, Klebsiella pneumoniae and was compared with Chloramphenicol as standard drug.[35]

Reagents and conditions: (a) CNBr, CH3OH, reflux, 34h Patel et al (2010) reported synthesis of benzimidazolyl1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl)acetamides as antibacterial, antifungal and anti-tuberculosis agents. 1,3,4-oxadiazoles were synthesized and assessed in vitro for their efficacy as antimicrobial agents against eight bacteria Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri. Compound with bromine and with fluorine on benzothiazole ring appeared with potential inhibitory efficacy against Staphylococcus aureus.[34]

Where R is H, NO2, CN, Br, I, OC2H5, CH3 Farshori et al (2011) synthesized 5alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4oxadiazoles and tested for in vitro antimicrobial activities by disc diffusion method.

Parkash et al (2010) synthesised some novel 2substituted-5-[isopropylthiazole] clubbed 1,3,4oxadiazoles (92 and 93) and tested for antimicrobial activity by broth microdilution method. Among the various synthesised compounds, compound 92 showed improved antibacterial activity against tested Grampositive bacteria i.e. Staphylococcus aureus, Staphylococcus faecalis, Bacillus subtillis and compound 92b having p-methoxy substitution showed excellent antifungal activity against Saccharomyces cerevisiae, Candida tropicalis, Aspergillus Niger. Compound 92a exhibited good inhibition against Gram-positive bacteria. These tested compounds were compared with standard drugs i.e. Ciprofloxacin, Norfloxacin, Flucanozole.[36]

Zhang et al (2006) reported the synthesis, biological evaluation, and molecular docking studies of 1,3,4oxadiazole derivatives possessing 1,4-benzodioxan moiety as potential anticancer agents. All the synthesized 1,3,4-oxadiazole derivatives 94a–94e were evaluated for their anti-proliferative activity. The bioassay tests demonstrated that compounds 94k, 94l, 94m, exhibited broad-spectrum antitumor activity. Among these compounds, compound 94j displayed the most potent anti-tumor activity.[37] Compound No.

R

Compoun d No.

R

94a

Ph-

94i

4-ClC6H4

94j

4-I-C6H4

94b 94c

Among the synthesised compounds, compound 91b was found to be more active against fungal strain i.e. Penicillium marneffei and was compared with Greseofulvin as standard drug. 91c, 91d were found to be more active against bacterial strains i.e. Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa,

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3CH3C6H44-NO2C6H4

94k

94d

2-F-C6H4

94l

94e

2-NO2C6H4

94m

2-CH3C6H4 2-BrC6H4 3-BrC6H4

94

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Abu-Zaied et al (2011) synthesized new oxadiazole thioglycosides and tested for in vitro anti-tumor activity. The two cell lines used in the present investigation are MCF-7 (breast) and HEPG2 (liver). From the tested cmpounds, it was observed that oxadiazole carrying two substituents (95b and 95c) especially when contain thioglycosidic linkage at C2 are more active than those carrying one substituent (95a). Compound 95b and 95c showed very good anticancer activity in terms of growth inhibitory effect on both cancer cell lines. Standard drug used for breast cancer was tamoxifen and standard drug for liver cancer was 5-flurouracil.[38] Compound No.

R

Compound No.

95a

H

95b

Kumar et al (2010) synthesized some novel 2substituted-5-[isopropylthiazole] clubbed 1,3,4oxadiazole (96 and 97) and tested for anti-tubercular activity. The MIC of each drug was determined by broth dilution assay. From the tested compounds, compound 96 and 97 showed excellent activity against M. tuberculosis. Standard drug was Isoniazid.[39]

96

95

R

Compound No.

R

95c

CH3-S-CH2-

Chandrakantha et al (2010) synthesized some novel 1,3,4-oxadiazole bearing 2-flouro-4-methoxy phenyl moiety and tested for antimicrobial activity by serial dilution method. Among the various synthesized compounds, compound 99a, 99b showed excellent antibacterial activity against Escherichia coli and Pseudomonas aeruginosa and 99c, 99d showed excellent antifungal activity against Candida albicans. Compounds tested for antibacterial activity was compared with standard drug Furacin and for antifungal activity standard drug was Flucanozole.[41]

97

Zheng et al (2010) synthesized 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moeity and tested for anti-tumor activity. Anti-proliferative assay results indicated that compound 98a and 98b exhibited the most potent activity against gastric cancer cell SGC7901. Compound 98a exhibited significant telomerase inhibitory activity which was comparable to the positive control ethidium bromide. 5-Flurouracil was used as a positive control.[40]

98 Compound No.

R

Compound No.

R

98a

2-OH4OCH3C6H3-

98b

Napthalene

Mishra et al (2010) synthesized a series of oxadiazole and then final compounds were tested for their antimicrobial activity by cup and plate method. Among the tested compound, compound 100a showed promising antibacterial activity against Gram +ve bacteria i.e. Streptococcus pneumonia and compound 100b showed promising anti-bacterial activity against Gram–ve bacteria i.e. Escherichia coli as compared to standard drugs Ofloxacin and Levofloxacin.[42]

100

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100a: R= 4-OCH3C6H5

100b: R= 4-NO2C6H5

compounds was screened agaist Helianthus annuus and Digitaria sanguinalis as a measure of herbicidal activity and Pyricularia oryzae, Septoria tritici for fugicidal activity. While none of the compound show good herbicidal and fugicidal activity. Standard for fungicidal activity was Azoxystrobin. From the sixteen compounds, compound 105a, 105b, 105c, 105d passed the HTS insect screens against larvae of Spodoptera exigue. However further testing of the four compounds in secondary assays against larvae of Spodoptera exigua and Helicoverpa Zea showed no activity when compared to the insecticidal standard Spinosad.[45]

Gilani et al (2010) synthesized 1,3,4-oxadiazole derivatives of Isoniazid (101 and 102) and tested for antiinflammatory and analgesic activity. From the tested compounds, compound 101 having 2,4-dichlorophenyl group at second position have highest anti-inflammatory and analgesic activity. When the phenyl group was replaced by mercapto group (102) the activity was found to be moderate. Ibuprofen was used as a standars drug.[43]

101

Compound No. 105a 105b 105c 105d

102

R1 3-Cl-C6H4 3-Cl-C6H4 3-Cl-C6H4 4-Cl-C6H4

R2 CH3 CH3 CH3 CH3

R3 4-Cl-C6H4 3-Cl-C6H4 2,6-Di-Cl-C6H3 3-Cl-C6H4

Mallikarjuna et al (2009) synthesized oxadiazole derivatives (103 and 104) and tested for their antitubercular activity. From the tested compounds, compound 103, 104a, 104b, 104c, 104d show better activity against M. tuberculosis. Standard drug was Isoniazid.[44] 105

103

Karthikeyan et al (2008) synthesized 2,4-dichloro-5flourophenyl containing oxadiazoles (106 and 107) and then final compounds were tested for their antimicrobial activity. Among the tested compounds, compound 106a, 106b, 106c, 106a, 106b and 106c showed good inhibition against Staphylococcus aureus, Escherichia coli. Compounds 107a, 107b, 107c, 107b and 107c ehibited good antibacterial activity almost equal to the standard i.e Ciprofloxacian. Compound 124c showed good bactericidal activity against Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae bacterial strains. Compound 106a, 106c, 106c showed good inhibition against all the fungal strains. Compound 106c showed good fungicidal activity against Candida albicans, Aspergillus fumigatus and Penicillium marneffei fungal strains and compared with standard drug Greseofluvin.[46]

104

Compound No.

R

Compound No.

R

104a

C6H5

104b

3,4,5(OCH3)3C6H2

104c

4N(CH3)2C6H4

104d

4-OHC6H4

Milinkevich et al (2009) synthesized 2-(4,5dihydroisoxazol-5-yl)-1,3,4-oxadiazoles (105). Sixteen compounds were synthesized and screened broadly for herbicidal, fungicidal and insecticidal activity. This set of Compound No.

R

Compound No.

R

Compound No.

R

106a

4CH3

106b

2CH3

106c

4-Cl-2CH3

106

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Compound No. 107a

R 2-Cl

Compound No. 107b

R 4-Cl

Compound No. 107c

R 2,4-Cl2

Joshi et al (2008) synthesized some oxadiazole derivatives (109) and tested for antitubercular activity. The MIC of each drug was determined by broth dilution assay. From the tested compounds, compound 109 showed highest activity. Standard drug was Isoniazid.[48]

107 109 Liu et al (2008) synthesized sulfoxide derivatives containing trimethoxyphenyl substituted 1,3,4oxadiazole moiety (108) and tested for their antifungal activity. From the data it was obtained that introduction of 1,3,4-oxadiazole in sulfoxide might improve their antifungal activities. Among the tested compounds, compound 126 was found to be more active against G. zeae, F. oxysporum and C. mandshurica than other ones. Hymexazol was used as standard drug.[47]

Amir et al (2007) synthesized some 1,3,4-oxadiazole derivatives (110) and tested for its anti-inflammatory activity by carrageenan-induced hind paw edema method. From the tested compounds, compound 110a and 110d showed maximum anti-inflammatory activity. Compound 110b and 110c were found with minimum activity. These compounds were compared with the standard drug Ibuprofen.[49]

108

110

Compound No. 110a 110c

R 2,4-Cl2C6H3 4-NO2C6H4

Compound No. 110b 110d

Hussain et al (2006) synthesized novel 5-(2hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4oxadiazol-2-thione derivatives and tested against cancer cells. From the tested compounds, compound 111a, 111b, 111c, 111d, 111e, 111f, 111g showed nonselective broad spectrum and promising activity against all cell lines. Compound 111b and 111c proved to be the most promising derivatives and also have less toxicity and ease of synthesis makes them promising lead compounds for cancer chemotherapy.[50] Compound No. 111a 111b 111c 111d 111e 111f 111g

R -NH-C6H4(2-Cl) -NH-C6H4(3-Cl) -NH-C6H4(4-Cl) -NH-C6H4(2-COOH) -NH-C6H4(4-COOH) -NH-C6H4(4-COCH3) -NH-C6H3(2-OH-4-COOH)

111

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